By Noreen Roth Henig, M.D., chief medical officer, Kezar Life Sciences
In drug development, we are always learning what we can do better. This is especially true when it comes to designing clinical trials. While novel drugs are designed and developed with patients in mind, it is increasingly important to ensure that patients understand how the new therapy will help them and how the burden of treatment justifies the benefit to them. Each time the clinical planning process is initiated there's an opportunity to re-learn that patients are truly individuals. Not only do patients with complex disease often respond differently to a new drug, but the individual’s experience of the new drug may also be different. What may present as a challenging impact of disease for some may not bother other patients. We are seeing an industry-wide trend in drug development that is personalized for the patient. Personalized gene therapies and cancer treatments can be target-specific, but consideration of individual experience is also a form of personalization. This trend can be at odds with regulatory bodies that desire the least amount of variability in patient populations when reviewing clinical trial designs. It’s understandable. Introducing variability makes data analysis much more complex. Industry and regulators can agree, though, that from a public health perspective, ultimately, we are trying to provide the most benefit to the greatest number of patients and this factors in to how we design clinical trials.
Balancing the needs of individual patients with providing benefit to the majority is just one part of the planning process when laying out a clinical trial design. At Kezar, we often begin by understanding the patient mindset first. Specifically, with patients who have aggressive chronic disease or a rare disease, our team starts by imagining what the patient profile might be. We ask, for example, what sort of treatments already exist and what they might wish their current medication was doing to manage their disease but is not. Why would it be prescribed, what reason would their physician give to take it, and what should they expect in terms of results and side effects? When starting a new treatment, patients want to understand how it will be administered and how long it might be until they see results.
1. Patients And Physicians Are Solving For Different Problems
But there’s another layer to this balancing act. In addition to the various needs of patients, we also have to address the greatest concerns expressed by physicians. Here’s a case in point. Before we initiated our Phase 2 lupus nephritis study, through our work with patient organizations we were able to hear almost directly from patients about their disease burden. For many patients with LN what bothers them most about their disease is fatigue, skin rashes, and the associated muscle and joint stiffness. Often LN affects young women who are trying to work and raise families, so they are very interested in treatments that can alleviate the impact LN has on day-to-day life. For physicians treating patients with LN, the priority is long-term health, and this means protecting the kidneys. The ultimate treatment goal is to keep patients off dialysis.
For a new treatment to meet the needs of both patients and physicians, we needed to study our drug’s ability to protect kidney health for the long term but also understand how it might address some of the more immediate disease impacts like fatigue, skin rash, and arthritis. Sometimes in clinical trials, you name the things easiest to measure – especially with diseases where every patient has a slightly different manifestation of the disease and people tend to experience it differently. We started by screening for trial participants who share commonality in the expression of their disease in order to demonstrate that the drug could make a meaningful difference. Knowing that a long-term devastating effect of LN is kidney failure, we set out to measure our drug’s ability to reduce protein in the urine, which is an indicator of kidney function and, fortunately, an objective endpoint that’s easy to measure.
In order to meet the immediate treatment goals of patients, we then made a further investment to also collect data on secondary conditions such as fatigue, rash, and arthritis to further understand what the drug can do. We believe that this data is just as important as the kidney specific data because it matters to patients and may help them make a more informed decision about their treatment
2. Trials Must Be Designed For Patient Comfort And Tolerability
Tolerability is another aspect we look to understand early on in a clinical trial – because it matters to patients. In every treatment there is a risk-benefit ratio that needs to be considered. Many patients with life-threatening cancers, for example, are willing to withstand treatments with rough side effects if they will extend or save their lives. For milder diseases that are not life-threatening, the treatment has to ease symptoms without causing new unwanted side effects. The treatment has to be proportional and relevant to the disease it is addressing.
As an example, at Kezar, we noticed that patients often felt nauseated with introduction of our investigational drug. We explored different ways of mitigating this and landed on a strategy where patients receive a low dose as the initial dose and then the weekly dose thereafter is at the investigational dose. This strategy did make a difference. And it was good for everyone – patients felt able to fully participate in the trial, and it is a strategy that we can use in future trials. Often, an investigator in the trial might flag times of day that are optimal for dosing in the early phases of a clinical trial. We learn a lot in the early studies about the pharmacodynamics of a drug and how to make it more tolerable. With these insights, we can optimize dosage, frequency of administration, and even formulation in some case. And we know whether we need to add supportive therapies for better tolerability.
3. We Need To Improve Issues Brought To Light By The Pandemic
Looking ahead to how clinical trials may change in the next decade, we can’t ignore the impact of the pandemic. In the last year and half, we’ve learned how to conduct clinical trials differently. We better understand the importance of global coordination and the need to be agile and adaptable about the way we run clinical trials and collect data. The fact that daily life can change in a heartbeat has been made real to the entire population. Our ability to identify fit for purpose treatments (such as RNA therapeutics) and use AI to generate thousands of sequences in a short time period has been honed for the next time.
The importance of education, and the negative impact of misinformation campaigns about science, and its ability to lead us out of the pandemic will not be forgotten. As industry leaders, we must continue to advocate for transparency and truth in order to develop good medicines for untreatable disease and build trust in science’s ability to solve unmet needs. We must not let those who have been marginalized and disenfranchised be left behind. We need to give patients seeking new treatment options reasons to believe that despite a broken healthcare system, the U.S. leads the world in medical innovation.
As we look to the future of clinical trial design, we must continue to increase engagement, convenience, and accessibility for those seeking to participate in clinical trials. It’s in our best interest to reach and recruit clinical trial participants who reflect the diversity of our world. Only with broad participation in clinical trials can we design better treatments that will have a meaningful impact for individuals and the greater public.
About The Author:
Noreen Roth Henig, M.D., is the Chief Medical Officer of Kezar Life Sciences. Her career spans clinical practice, academic medicine, translational science, clinical development, and medical and regulatory affairs. Prior to joining industry, Henig spent nearly 10 years in leadership roles within academic medicine at Stanford University and California Pacific Medical Center. She is a board-certified physician in pulmonary and critical care, and board eligible in allergy and immunology.